Abstracts

Rationale: While lamotrigine is an effective, often well-tolerated antiseizure medication (ASM), a recent warning based on in vitro data raised the possibility of inducing ventricular arrhythmias. To better characterize this potential risk, we compared arrhythmia incidence between patients newly treated for seizures with lamotrigine versus levetiracetam (a presumed cardiac-inert “control” ASM).

Methods: We included patients whose first ASM fill was on or after the date of the first seizure or epilepsy ICD code in the study period, with no ASM in the prior year. We conducted parallel retrospective cohort studies using two independent datasets: 1) 2009-2018 Medicare claims from the United States, and 2) Clinical Practice Research Datalink (CPRD) data under the CALIBER programme, a population-based cohort in the United Kingdom. We examined standardized cumulative incidence curves primarily for ventricular tachycardia or fibrillation (VT/VF) from Cox proportional hazard models for patients whose first ASM was lamotrigine compared to levetiracetam over a two-year follow-up period.

Results: We included 40,554 patients (lamotrigine: 3,038; levetiracetam: 37,516) from Medicare and 13,098 (lamotrigine: 8,694; levetiracetam: 4,404) from CPRD data. After adjusting for demographics and relevant cardiac and neurological comorbidities and medication use, the hazard ratio for VT/VF comparing patients whose first ASM was lamotrigine versus levetiracetam was 0.73 (95% CI 0.50-1.1) for Medicare and 0.75 (95% CI 0.35-1.59) for CPRD, with a two-year cumulative incidence of 1.7% (95% CI 1.0%-2.3%) versus 2.3% (95% CI 2.1%-2.4%) for Medicare and 0.2% (95% CI 0.1%-0.4%) versus 0.3% (95% CI 0.2%-0.6%) for CPRD data. In both datasets, lamotrigine had a slightly but nonsignificantly lower 2-year cumulative incidence of VT/VF compared with levetiracetam (Medicare: absolute difference -0.6%, 95% CI -1.2% to 0.0%; CPRD: absolute difference -0.1%, 95% CI -0.3% to 0.1%). We conducted a wide array of sensitivity analyses modifying the outcome (atrial arrhythmias or any arrhythmias), censorship procedure (additionally censoring patients upon discontinuing their initial ASM), or population (patients with existing cardiovascular diagnoses), none of which found increased arrhythmias in the lamotrigine group.

Conclusions: The incidence of serious ventricular arrhythmias was similar between patients newly treated with lamotrigine versus levetiracetam. These data call into question the recent warning regarding lamotrigine’s possible proarrhythmia effects.

Funding: This work did not receive direct study funding. Dr Terman is supported by the American Epilepsy Society Research and Training Fellowship for Clinicians.